1. Field of the Invention
The present invention relates to a novel antibody specifically binding to human and mouse L1CAM, and more particularly, to an antibody binding to both human and mouse L1CAM with high affinity, which is prepared by modifying a sequence of an L1 cell adhesion molecule (L1CAM)-specific antibody including a heavy-chain variable region of SEQ ID NO. 1 and a light-chain variable region of SEQ ID NO. 5, a polynucleotide encoding the antibody, an expression vector including the polynucleotide, a transformant introduced with the vector, a pharmaceutical composition for preventing or treating cancer including the antibody, a method for treating cancer using the antibody, a composition for diagnosing cancer including the antibody, a kit for diagnosing cancer including the composition, a method for providing information for cancer diagnosis using the antibody, and an antibody-drug conjugate prepared by conjugating a drug to the antibody.
2. Description of the Related Art
L1 cell adhesion molecule (L1CAM, CD171) is one of the immunoglobulin superfamily cell adhesion molecules (CAMs) that mediate cell-to-cell adhesion on the cell surface and is a glycoprotein having a molecular weight of 200 to 220 kDa. L1CAM was first known as a protein that mediates neuron-neuron adhesion and is involved in neurite outgrowth and neuronal migration (Lee et al., PNAS 74, 5021, 1977; McGuire and Greene 15, 357, 1978). Human L1CAM is a type 1 integral membrane glycoprotein which is composed of 1,257 amino acids and spans the cell membrane once, and its amino terminal portion exists outside the cell membrane and its carboxyl terminal portion exists in the cytoplasm. The extracellular domain contains six immunoglobulin type 2 domains, five fibronectin III-like domains, and twenty N-glycosylation sites.
Besides the highest expression in the normal human brain, L1CAM expression is also found in some hematopoietic cells and renal cells, peripheral nerves, and ganglions, but not found in other normal cells (Huszar et al., Human Pathology 37, 1000-1008, 2006). Recently, it has been reported that L1CAM overexpression is found in cancer cells such as melanoma, neuroblastoma, ovarian cancer, colon cancer, pancreatic cancer, and endometrial cancer, L1CAM plays an important role in the growth and metastasis of cancer cells, and L1CAM overexpression is associated with poor prognosis of cancer. For this reason, L1CAM has been emerged as a target in cancer therapy (Raveh et al., Cancer Letters 282: 137-145, 2009).
There have been many reports regarding diagnosis and treatment of cancer using L1CAM antibodies. For example, EP Patent No. EP1172654 and U.S. Pat. No. 7,618,785 disclose a method for the diagnosis and prognosis of ovarian or endometrial tumors, characterized in that L1CAM antibodies are used to determine the presence and level of L1CAM in a patient sample on the basis that presence of L1CAM is an indication of the presence of an ovarian or endometrial tumor, and a method of treating the tumors by administering a complex of the L1CAM antibody and a cytotoxic drug to the patient. Further, US Patent Publication No. 2004/0115206 discloses a method for inhibiting cell growth or inducing cell death in tumor cells by contacting the tumor cells with an effective amount of an anti-L1CAM antibody capable of inhibiting cell growth or inducing cell death in the tumor cells. Furthermore, International Patent Publication No. WO2006/013051 provides a composition inhibiting the L1CAM protein being overexpressed in ovarian and endometrial carcinoma and its expression, and a method for preventing and treating ovarian and endometrial carcinoma using the composition. This patent describes that a composition including an anti-L1CAM antibody or a derivative thereof suppresses functions of ovarian and endometrial carcinoma and blocks the migration of the cancer cells, thereby realizing treatment of cancer. Further, the present inventors demonstrated that L1CAM is expressed in cholangiocarcinoma and involved in proliferation and migration of cholangiocarcinoma cells, and growth of cholangiocarcinoma cells is inhibited by monoclonal antibody against L1CAM, suggesting that there is an association between L1CAM and cholangiocarcinoma (Korean Patent NOS. 10-756051 and 10-0931976).
However, L1CAM antibodies that have been developed until now are mouse antibodies, and thus there is a disadvantage that the antibodies bind to human L1CAM, but do not bind to mouse L1CAM. Usually, nude mice transplanted with human cancer cells are used in animal tests for anti-cancer efficacy of antibodies. In this regard, since antibodies that bind to human L1CAM but do not bind to mouse L1CAM bind to only human cancer tissues, but do not bind to L1CAM expressed in some normal tissues of a mouse, their anti-cancer efficacy and toxicity could not be accurately evaluated, compared to clinical trials in cancer patients. In order to solve this problem, there has been a demand for antibodies that bind to both human and mouse L1CAM with high binding ability and exhibit excellent anti-cancer efficacy. Thus, the present inventors developed L1CAM-binding antibodies having binding capacity to human and mouse L1CAM (Korean Patent Publication No. 10-2010-0064985). However, it is still necessary to develop an L1CAM antibody that binds to both human and mouse L1CAM with improved binding capacity.
Accordingly, the present inventors have made intensive efforts to develop an antibody that is cross-reactive with mouse and human L1CAM and has excellent binding capacity to L1CAM. As a result, they prepared an antibody with greatly improved affinity for both human and mouse L1CAM, compared to the existing antibodies, via mutations in particular amino acids of heavy chain and light chain variable regions of Ab4, and they found that this antibody has excellent anti-cancer efficacy, thereby completing the present invention.